Abstract Cancer immunotherapy is emerging as a new paradigm for the treatment of cancer by targeting the body's immune system instead of tumor. Clinical approvals of several check point inhibitors (e.g., Ipilimumab, Pembrolizumab) have shown durable response in a small subset of melanoma patients over conventional chemotherapy. Despite these successes, many cancers are poorly immunogenic and do not generate adequate cytotoxic T lymphocytes (CTLs) and therefore these patients cannot benefit from immune checkpoint therapies. The long-term goal of this application is to establish STING-activating polymeric nanovaccines for cytotoxic T cell therapy of melanoma. We will capitalize on the discovery of an ultra-pH sensitive polymer (PC7A) that allows optimal spatio-temporal orchestration of cytosolic delivery of tumor antigen (Ag) in dendritic cells and innate stimulation for the robust production of tumor-specific CTLs. A simple physical mixture of Ag-PC7A NP resulted in a robust Th1 and CTL (>80%) response without the need of innate stimulants (i.e., CpG, Poly(I:C)). Use of tumor associated antigens (TAAs) have shown significantly increased antitumor efficacy in a B16F10 melanoma model in mice. We will test the central hypothesis that PC7A nanoparticle vaccine will synergize with checkpoint inhibition to allow a safe and efficacious T cell therapy of melanoma. There are three specific aims: (1) Expand the nanovaccine platform to multiple melanoma peptide antigens; (2) Evaluate the safety of the polymeric nanovaccines in healthy, immunocompetent animals; and (3) Evaluate the antitumor efficacy of the polymer nanovaccines and its synergy with checkpoint inhibition. Accomplishments of the above aims will provide critical data for clinical translation of the nanovaccines for melanoma therapy. We will also collaborate with other nanoalliance members to test the PC7A NP in additional cancer indications.